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Submitted on August 21, 2006
Accepted on April 10, 2007
Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892, Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892, Microarray Facility, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20877, Department of Microbiology and Urology, New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, First Department of Pediatrics, Athens University Medical School, 11527 Athens, Greece
* To whom correspondence should be addressed. E-mail: kinot{at}mail.nih.gov.
Glucocorticoids, major end-effectors of the stress response, play an essential role in the homeostasis of the central nervous system and influence diverse functions of neuronal cells. We found that cyclin-dependent kinase 5 (CDK5), which plays important roles in the morphogenesis and functions of the nervous system and whose aberrant activation is associated with development of neurodegenerative disorders, interacted with the ligand-binding domain of the glucocorticoid receptor (GR) through its activators p35 or its active proteolytic fragment p25. CDK5 phosphorylated GR at multiple serines, including Ser203 and Ser211 of its N-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to DNA. In microarray analyses using rat cortical neuronal cells, the CDK5 inhibitor roscovitine differentially regulated the transcriptional activity of the GR on more than 90 percent of the endogenous glucocorticoid-responsive genes tested. Thus, CDK5 exerts some of its biologic activities in neuronal cells through the GR, dynamically modulating GR transcriptional activity in a target promoter-dependent fashion.
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